This invention relates to a new process for the production of a compound of cephamycin type and specifically of 7.beta.-[(2D-2-amino-2-carboxy)ethylthioacetamido]-7.alpha.-methoxy-3-[(1- methyl-1H-tetrazole-5-yl)thiomethyl]-3-cephem-4-carboxylic acid and a pharmaceutically acceptable salt thereof as well as a pharmaceutically acceptable ester thereof which possess a high antibacterial activity and find wide applications in chemotherapeutic treatment of bacterial infections.
The 7.beta.-[(2D-2-amino-2-carboxyl)ethylthioacetamido]-7.alpha.-methoxy-3-[(1 -methyl-1H-tetrazole-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (hereinafter referred to merely as "the object compound") was newly synthetized in the laboratory where the present inventors are working (see Japanese patent application unexamined publication "Kokai" No. 83791/80 published on 24th June 1980; Belgian Pat. No. 880,656; co-pending U.K. patent application No. 79 43159; and co-pending U.S. patent application Ser. No. 104,220). All of the methods of producing the object compound which were developed earlier are exclusively starting from 7-amino-cephalosporanic acid as the initial material and need in a certain stage to carry out some known procedures for the 7.alpha.-methoxylation of the 7-amino-cephalosporanic acid. The presently available procedures for the 7.alpha.-methoxylation usually need careful and troublesome operations and are accompanied inevitably by undesirable 7.beta.-methoxylation. The concomitance of the desired 7.alpha.-methoxylation product with even a slight amount of the undesired 7.beta.-methoxylation product normally can reduce very much the therapeutic effect and commerical value of the 7.alpha.-methoxylation product, and hence it is strongly demanded to remove the 7.beta.-methoxylation product from the 7.alpha.-methoxylation product. However, there is not yet obtained an efficient and facile method of purifying the 7.alpha.-methoxylation product to be freed from the concomitant 7.alpha.-methoxylation product which is available in a commercial scale. In these circumstances, we have seeked for a new process for the production of the object compound which is unnecessary in any stage to conduct the procedures for the 7.alpha.-methoxylation of 7-amino-cephalosporanic acid or a 7-amino-cephalosporine compound. Cephamycin A or B is the compound initially containing the 7.alpha.-methoxycephem nucleus which is produced as the fermentative product in the cultivation of some microorganisms belonging to the genus Streptomyces, and we have extensively studied in an attempt to provide a new process of producing the object compound which is able to start from cephamycin A or B and hence does not need the 7.alpha.-methoxylation taking place in any stage of the process. As a result, we have now found that when cephamycin A and/or cephamycin B are or is subjected to consecutive steps of reactions which are combined in an ingenious way as described hereinafter, the object compound can be produced in a facile way in a high yield. On the basis of these our findings, we have now devised the new process of this invention.
A principal object of this invention is to provide a new process whereby the desired object compound can be advantageously produced starting from cephamycin A, B but without necessity of the 7.alpha.-methoxylation step which has been required in the earlier methods starting from 7-amino-cephalosporanic acid.
Other objects and advantages of this invention will become apparent from the following descriptions.